rs79074685

Variant names:

• chr7-117548796-G-A
• rs79074685
• NM_000492.4:c.1365G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-117548796-G-A
• chr7-117548796-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000492.4(CFTR):​c.1365G>A​(p.Ala455Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,555,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A455A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -1.15
• Publications: 12 publications found

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 7-117548796-G-A is Benign according to our data. Variant chr7-117548796-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35820.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1365G>A	p.Ala455Ala	synonymous	Exon 10 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6257C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1365G>A	p.Ala455Ala	synonymous	Exon 10 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1365G>A	p.Ala455Ala	synonymous	Exon 10 of 27	ENSP00000514471.1
	CFTR	ENST00000889206.1		c.1365G>A	p.Ala455Ala	synonymous	Exon 10 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 209 AN: 128398 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000809

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000259

Gnomad FIN AF: 0.00121

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000677

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000465 AC: 107 AN: 229864 AF XY: 0.000345

Gnomad AFR exome AF: 0.00480

Gnomad AMR exome AF: 0.000154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00137

Gnomad NFE exome AF: 0.0000295

Gnomad OTH exome AF: 0.000356

GnomAD4 exome AF: 0.000185 AC: 264 AN: 1427304 Hom.: 0 Cov.: 35 AF XY: 0.000158 AC XY: 112 AN XY: 709802

African (AFR) AF: 0.00416 AC: 135 AN: 32414

American (AMR) AF: 0.000139 AC: 6 AN: 43230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24958

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37456

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85154

European-Finnish (FIN) AF: 0.00123 AC: 63 AN: 51048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.0000376 AC: 41 AN: 1089340

Other (OTH) AF: 0.000292 AC: 17 AN: 58152

GnomAD4 genome AF: 0.00164 AC: 211 AN: 128474 Hom.: 1 Cov.: 32 AF XY: 0.00166 AC XY: 104 AN XY: 62492

African (AFR) AF: 0.00562 AC: 195 AN: 34680

American (AMR) AF: 0.0000808 AC: 1 AN: 12378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3034

East Asian (EAS) AF: 0.00 AC: 0 AN: 4374

South Asian (SAS) AF: 0.000260 AC: 1 AN: 3850

European-Finnish (FIN) AF: 0.00121 AC: 10 AN: 8272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.0000677 AC: 4 AN: 59096

Other (OTH) AF: 0.00 AC: 0 AN: 1744

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.00130

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Cystic fibrosis (4)
-	1	2	not provided (3)
-	-	2	CFTR-related disorder (2)
-	-	2	not specified (2)
-	-	1	Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
-	-	1	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.1
DANN	Benign	0.52
PhyloP100		-1.1
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs79074685; hg19: chr7-117188850;